Abstract: Compelling evidence indicates that systemic factors in the blood profoundly reverse aging related impairments, as exposure of aged mice to young blood using parabiosis (an approach for exchanging systemic milieu) and/or transfusion is capable of rejuvenating stem cell function in muscle, liver, spinal cord and brain and improving cognitive function, and ameliorates cardiac hypertrophy. Very recent studies also showed that a healthy animal could extend life span of a partner exposed to a lethal treatment or disease. These findings suggest that systemic milieu of a healthy young partner may be beneficial for an aged organism. However, it is currently unknown whether a healthy systemic milieu contributes to functional recovery after ischemic stroke. Our preliminary study showed that intraperitoneal administration of young plasma into ischemic stroke rats significantly reduced infarct volume and ameliorated motor impairment, compared with vehicle group. On the contrary, intraperitoneal administration of old plasma into young ischemic rats worsened their brain injury and motor deficits. Using a proteomic approach, we identified several new factors affecting stroke recovery. Therefore, the central hypothesis of this proposal is that: (a) the neurological deficits after ischemic stroke in aged rats are reversible upon exposure to young systemic milieu and (b) the underlying mechanism is likely due to the altered levels of soluble systemic factors in the young and aged rats. Our SPECIFIC AIM is to determine the effect of young adult (3-month-old) and old (24-month-old) systemic environment on functional outcome of ischemic stroke rats, and identify the potential systemic factors affecting stroke recovery. The rationale for the proposed research is that successful completion of the proposed experiments will provide missing, fundamental knowledge regarding the impact of the systemic milieu on functional recovery of young and aged ischemic rats. Identifying beneficial and detrimental molecules from young and old blood may result in new and innovative approaches to prevent or treatment of a variety of aged-related diseases including stroke.